The overall objectives of this study are: (a) to elucidate the mechanism(s) of photodynamic therapy induced resistance by various photosensitizers and; (b) to investigate factors responsible for the varying degree of inherent sensitivity to photodynamic therapy in various human tumors. The research focus is based on the following primary hypotheses: (1) That the induction of resistance to PDT in tumor cells is dependent on the ability of cells to alter the stress signals. (2) The inherent modulate the oxidative stress mediated by PDT. (3) That the combination of photosensitizers with unique intracellular distribution may synergize the PDT induced phototoxicity. It would also ensure the responsiveness of heterogenous tumors to multiple intracellular targets. The project comprises several groups of experiments: (i) characterization of photosensitizer cellular/intracellular localization in parent and PDT- induced resistant variants in vitro; (ii) assessment of subcellular targets of PDT induced photocytotoxicity in parent and resistant variants in vitro; (iii) examination of pathways involved in PDT mediated responsiveness of cells, in particular the pathways for recovery of PDT - induced damage including DNA repair pathways; (iv) investigation of the role of PDT induced cell examination of the role of chaperones on PDT - induced oxidative stress in human tumor cells; and (vii) examination of the importance of mitochondrial-bound hexokinases. The selection of in vitro PDT - induced resistant variants is expected to amplify the biochemical or other intracellular changes associated with resistance. This, and the degree of cross-resistance between the photosensitizers are expected to provide clues as to the mechanisms of action of photosensitizers in vitro.